EP0302145A2 - Verfahren zur Herstellung von kristallinem Cefadroxilmonohydrat - Google Patents

Verfahren zur Herstellung von kristallinem Cefadroxilmonohydrat Download PDF

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Publication number
EP0302145A2
EP0302145A2 EP87119079A EP87119079A EP0302145A2 EP 0302145 A2 EP0302145 A2 EP 0302145A2 EP 87119079 A EP87119079 A EP 87119079A EP 87119079 A EP87119079 A EP 87119079A EP 0302145 A2 EP0302145 A2 EP 0302145A2
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EP
European Patent Office
Prior art keywords
cefadroxil
solvate
monohydrate
water
crystalline
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP87119079A
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English (en)
French (fr)
Other versions
EP0302145B1 (de
EP0302145A3 (en
Inventor
Leonardo Marsili
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Rifar SRL
Original Assignee
Rifar SRL
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Filing date
Publication date
Application filed by Rifar SRL filed Critical Rifar SRL
Priority to AT8787119079T priority Critical patent/ATE105560T1/de
Publication of EP0302145A2 publication Critical patent/EP0302145A2/de
Publication of EP0302145A3 publication Critical patent/EP0302145A3/en
Application granted granted Critical
Publication of EP0302145B1 publication Critical patent/EP0302145B1/de
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D501/14—Compounds having a nitrogen atom directly attached in position 7
    • C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
    • C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
    • C07D501/22—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with radicals containing only hydrogen and carbon atoms, attached in position 3
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents

Definitions

  • the present invention relates to an effective method for preparing crystalline cefadroxil monohydrate.
  • Cefadroxil is a well known antibiotic substance having antibacterial activity: it is disclosed and claimed in the U.S. patent no. 3,489,752 according to which it is obtained by acylation of 7-ADCA with an amino-protected derivative of D(-)-alpha-p­-hydroxyphenylglycine.
  • 3,985,741 discloses prepara­tion of cefadroxil by acylation of 7-ADCA with mixed anhydride of D-(-)-alpha-p-hydroxyphenylglycine when the latter's alpha-amino group has been blocked with a beta-keto compound such as methyl acetoacetate: the reaction mixture is first added with water and then with dimethylformamide to precipitate a crystallized solvate of cefadroxil having more than 3% of water content which, after filtration, is slurried in 90% methanol.
  • the so obtained cefadroxil crystals have a high methanol content,what is pharmaceutically unacceptable because such alcohol is toxic.
  • cefadroxil aqueous solution can be prepared following the procedures described in Example XVI of the European patent application no. 001,133, or in Examples 1 and 2 of the U.K. patent application no. 2,064,511 or in Examples 1 to 4 of the U.S. patent no. 4,234,721.
  • the crystalline cefadroxil monohydrate is prepared by slurrying the cefadroxil DMF solvate with water or a water/solvent mixture. If water alone is used, the obtained product contains impurities as it is confirmed by what is written in lines 41-44 of col. 8 of Re 31,730: moreover the yield is low.
  • cefadroxil DMF solvate in addition to the known cefadroxil DMF solvate, also other novel cefadroxil solvates can be used, which are the cefadroxil solvates of dimethylacetamide, of N-methyl-2-pyrrolidone and of monomethylformamide.
  • the present invention concerns a method for producing crystalline cefadroxil monohydrate, according to which a cefadroxil solvate is slurried with isopropyl alcohol containing from about 6% to 18% W/W of water, at a temperature in the range of about +45°C to +55°C and for a time between 1 to 2 hours, the crystalline cefadroxil monohydrate being then isolated by filtration.
  • the cefadroxil solvate can be a solvate of dimethylacetamide, of N-methyl-2-pyrrolidone and of monomethylformamide which can be prepared by adding to an aqueous solution of cefadroxil just obtained from 7-ADCA a solvent selected from the group consisting of dimethylacetamide, N-methyl-2-pyrrolidone, monomethylformamide, while controlling the pH of the solution in the range 5.5-6, to give the corresponding cefadroxil solvate which precipitates and is filtered off.
  • Dimethylaniline (31 g) and D(-)-p-hydroxyphenylglycyl chloride hydrochloride hemidioxane solvate (63g) were added and the mixture was stirred at -5°C/0°C for about 90′.
  • the aqueous phase was diluted with dimethylacetamide (350 ml) and the pH was adjusted to 6.0 by slowly adding diethylamine at 25°C. The mixture was stirred at 20°C for 120′.
  • 7-ADCA (21.5g) was charged at +5°C into water (50 ml) and dimethylsuphoxide (90 ml) and triethylamine (11.3 g) were added. The obtained solution was cooled to 0°C and the suspension of mixed anhydride (at -55°C) was added to the solution of 7-ADCA.
  • Cefadroxil dimethylacetamide solvate (40 g) prepared according to example 1 was slurried in aqueous isopropyl alcohol (200 ml) containing 13% W/W of water at 50°C for 90′. The mixture was cooled to +5°C and cefadroxil monohydrate was collected to yield 28.5 g exhibiting the same X-ray diffraction pattern of an authentic sample of crystal­line cefadroxil monohydrate. K.F. 4.7% HPLC Assay: 98.4% on dry basis.
  • Cefadroxil 1-methyl 2-pyrrolidone solvate (30 g) prepared according to example 4 was slurried in aqueous isopropyl alcohol (150 ml) containing 10 ml of water at 50°C-52°C for 120′.
  • the mixture was cooled to +5°C and then filtered.
  • Cefadroxil monomethylformamide solvate 50 g prepared accord­ing to example 3 and having K.F. 1.4% was slurried in aqueous isopropyl alcohol (250 ml) containing 40 ml of water at 48°C for 150′. The mixture was cooled to +2°C and crystalline cefadroxil monohydrate was collected. Yield: 40.8 g K.F.: 5.2% HPLC Assay: 99.2% on dry basis.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Communicable Diseases (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Oncology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Cephalosporin Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
EP87119079A 1987-08-03 1987-12-22 Verfahren zur Herstellung von kristallinem Cefadroxilmonohydrat Expired - Lifetime EP0302145B1 (de)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AT8787119079T ATE105560T1 (de) 1987-08-03 1987-12-22 Verfahren zur herstellung von kristallinem cefadroxilmonohydrat.

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US80999 1987-08-03
US07/080,999 US4898938A (en) 1987-08-03 1987-08-03 Method for preparing crystalline cefadroxil monohydrate

Publications (3)

Publication Number Publication Date
EP0302145A2 true EP0302145A2 (de) 1989-02-08
EP0302145A3 EP0302145A3 (en) 1989-08-23
EP0302145B1 EP0302145B1 (de) 1994-05-11

Family

ID=22161022

Family Applications (1)

Application Number Title Priority Date Filing Date
EP87119079A Expired - Lifetime EP0302145B1 (de) 1987-08-03 1987-12-22 Verfahren zur Herstellung von kristallinem Cefadroxilmonohydrat

Country Status (18)

Country Link
US (1) US4898938A (de)
EP (1) EP0302145B1 (de)
JP (1) JP2655664B2 (de)
KR (1) KR960002910B1 (de)
CN (1) CN1016607B (de)
AT (1) ATE105560T1 (de)
AU (1) AU597136B2 (de)
CA (1) CA1285554C (de)
DE (1) DE3789810T2 (de)
DK (1) DK680387A (de)
ES (1) ES2056059T3 (de)
FI (1) FI88043C (de)
NO (1) NO168425C (de)
PH (1) PH23648A (de)
PT (1) PT86526B (de)
RU (1) RU1804461C (de)
YU (1) YU44649B (de)
ZA (1) ZA879701B (de)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991000865A1 (en) * 1989-07-10 1991-01-24 Gema S.A. A novel stable form of cephradine, process for its production and intermediates used therein

Families Citing this family (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5589593A (en) * 1991-11-11 1996-12-31 Biochimica Opos Spa Crystalline form of a cephalosporin antibiotic
IT1251999B (it) * 1991-11-11 1995-05-27 Opos Biochimica Srl Forma cristallina di un antibiotico cefalosporinico
JP2005530746A (ja) * 2002-05-03 2005-10-13 エスビー・ファルムコ・プエルト・リコ・インコーポレイテッド カルベジロールファーマソルブ溶媒和物
US20040077849A1 (en) * 2002-10-16 2004-04-22 Orchid Chemicals & Pharmaceuticals Limited Process for the preparation of cefadroxil
US7842791B2 (en) * 2002-12-19 2010-11-30 Nancy Jean Britten Dispersible pharmaceutical compositions
CN1311830C (zh) * 2004-02-27 2007-04-25 石药集团中奇制药技术（石家庄）有限公司 头孢羟氨苄口腔崩解片及其制备方法
KR101420451B1 (ko) * 2006-05-19 2014-07-16 디에스엠 시노켐 파마슈티칼스 네덜란드 비.브이. 세파드록실의 결정화 방법
CN102134250B (zh) * 2011-01-19 2013-03-13 天津大学 一种头孢羟氨苄单水合物的结晶方法及结晶
CN104447795B (zh) * 2014-11-28 2016-08-17 珠海金鸿药业股份有限公司 一种头孢羟氨苄化合物及其药物组合物
CN105534937B (zh) * 2015-12-30 2019-12-03 石药集团欧意药业有限公司 一种头孢羟氨苄片剂及其制备方法
CN106588953B (zh) * 2016-11-08 2018-11-27 山东罗欣药业集团恒欣药业有限公司 一种抗感染药物头孢羟氨苄晶型化合物及其组合物
CN106588954B (zh) * 2016-11-08 2018-11-27 山东罗欣药业集团恒欣药业有限公司 一种抗感染药物羟氨苄晶体化合物及其组合物

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2349589A1 (fr) * 1976-04-27 1977-11-25 Bristol Myers Co Procede de preparation d'une cephalosporine et produit obtenu
US4160863A (en) * 1977-04-07 1979-07-10 Bristol-Myers Company Process for the preparation of the crystalline monohydrate of 7-[D-α-aα-(p-hydroxyphenyl)acetamido]-3-methyl-3-cephem-4-carboxylic acid

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB8714180D0 (en) * 1987-06-17 1987-07-22 Rifar Srl Anhydrous crystalline cefadroxil
WO1988008320A1 (en) * 1987-04-24 1988-11-03 Invenmark Limited Puzzle

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2349589A1 (fr) * 1976-04-27 1977-11-25 Bristol Myers Co Procede de preparation d'une cephalosporine et produit obtenu
FR2365570A1 (fr) * 1976-04-27 1978-04-21 Bristol Myers Co Monohydrate cristallin de cefadroxile et son procede de preparation
US4160863A (en) * 1977-04-07 1979-07-10 Bristol-Myers Company Process for the preparation of the crystalline monohydrate of 7-[D-α-aα-(p-hydroxyphenyl)acetamido]-3-methyl-3-cephem-4-carboxylic acid

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991000865A1 (en) * 1989-07-10 1991-01-24 Gema S.A. A novel stable form of cephradine, process for its production and intermediates used therein

Also Published As

Publication number Publication date
AU597136B2 (en) 1990-05-24
PT86526A (pt) 1989-09-14
DK680387A (da) 1989-02-04
EP0302145B1 (de) 1994-05-11
DK680387D0 (da) 1987-12-22
CN1031085A (zh) 1989-02-15
PT86526B (pt) 1994-10-31
NO880026L (no) 1989-02-06
NO168425B (no) 1991-11-11
JPS6442487A (en) 1989-02-14
DE3789810D1 (de) 1994-06-16
ATE105560T1 (de) 1994-05-15
CN1016607B (zh) 1992-05-13
AU8304587A (en) 1989-02-09
DE3789810T2 (de) 1994-08-18
FI88043B (fi) 1992-12-15
PH23648A (en) 1989-09-27
FI881040A (fi) 1989-02-04
NO880026D0 (no) 1988-01-05
NO168425C (no) 1992-02-19
CA1285554C (en) 1991-07-02
YU242787A (en) 1989-02-28
US4898938A (en) 1990-02-06
FI88043C (fi) 1993-03-25
ES2056059T3 (es) 1994-10-01
KR960002910B1 (ko) 1996-02-28
KR890003775A (ko) 1989-04-18
ZA879701B (en) 1988-06-23
YU44649B (en) 1990-10-31
JP2655664B2 (ja) 1997-09-24
FI881040A0 (fi) 1988-03-07
EP0302145A3 (en) 1989-08-23
RU1804461C (ru) 1993-03-23

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